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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >A protective role for CD154 in hepatic steatosis in mice.
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A protective role for CD154 in hepatic steatosis in mice.

机译：CD154在小鼠肝脂肪变性中的保护作用。

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摘要

Inflammation and lipid metabolism pathways are linked, and deregulation of this interface may be critical in hepatic steatosis. The importance of the dialog between inflammatory signaling pathways and the unfolded protein response (UPR) in metabolism has been underlined. Herein, we studied the role of CD154, a key mediator of inflammation, in hepatic steatosis. To this end, Balb/c mice, wild-type or deficient in CD154 (CD154KO), were fed a diet rich in olive oil. In vitro, the effect of CD154 was studied on primary hepatocyte cultures and hepatocyte-derived cell lines. Results showed that CD154KO mice fed a diet rich in olive oil developed hepatic steatosis associated with reduced apolipoprotein B100 (apoB100) expression and decreased secretion of very low-density lipoproteins. This phenotype correlated with an altered UPR as assessed by reduced X-Box binding protein-1 (XBP1) messenger RNA (mRNA) splicing and reduced phosphorylation of eukaryotic initiation factor 2alpha. Altered UPR signaling in livers of CD154KO mice was confirmed in tunicamycin (TM) challenge experiments. Treatment of primary hepatocyte cultures and hepatocyte-derived cell lines with soluble CD154 increased XBP1 mRNA splicing in cells subjected to either oleic acid (OA) or TM treatment. Moreover, CD154 reduced the inhibition of apoB100 secretion by HepG2 cells grown in the presence of high concentrations of OA, an effect suppressed by XBP1 mRNA silencing and in HepG2 cells expressing a dominant negative form of inositol requiring ER-to-nucleus signaling protein-1. The control of the UPR by CD154 may represent one of the mechanisms involved in the pathophysiology of hepatic steatosis. Conclusion: Our study identifies CD154 as a new mediator of hepatic steatosis.
机译：炎症和脂质代谢途径是相关的，该界面的失调在肝脂肪变性中可能至关重要。人们强调了炎症信号通路与新陈代谢中未折叠的蛋白质反应（UPR）之间对话的重要性。本文中，我们研究了炎症关键介质CD154在肝脂肪变性中的作用。为此，向野生型或缺乏CD154（CD154KO）的Balb / c小鼠喂食富含橄榄油的饮食。在体外，研究了CD154对原代肝细胞培养物和肝细胞衍生细胞系的影响。结果表明，喂食富含橄榄油的饮食的CD154KO小鼠会发生肝脂肪变性，伴载脂蛋白B100（apoB100）表达降低，极低密度脂蛋白分泌减少。通过减少X-Box结合蛋白1（XBP1）信使RNA（mRNA）剪接和减少真核生物起始因子2alpha的磷酸化评估，该表型与UPR改变有关。在衣霉素挑战实验中证实了CD154KO小鼠肝脏中UPR信号的改变。用可溶性CD154处理原代肝细胞培养物和肝细胞衍生的细胞系会增加XBP1 mRNA在接受油酸（OA）或TM处理的细胞中的剪接。此外，CD154降低了在高浓度OA存在下生长的HepG2细胞对apoB100分泌的抑制作用，这种作用被XBP1 mRNA沉默抑制，并且在表达需要ER到核信号蛋白1的肌醇显性阴性形式的HepG2细胞中抑制。 。 CD154对UPR的控制可能代表了肝脂肪变性的病理生理机制之一。结论：我们的研究确定CD154是肝脂肪变性的新介体。

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